Nitric oxide (NO) is a highly reactive molecule implicated in numerous physiological and pathological processes. The role of NO in vasodilatation, neurotransmission and immunity is complex in many aspects (Tarr 2006). This molecule is also known as the main actor of nonspecific anti-tumor immune responses (Roshni 2003). However, recent studies show that interplay with cancer cells is more complex than it was believed to be before. NO is able to inhibit, but also to promote, tumor expansion and metastases (Tarr 2006, Lechner 2005). The outcome of tumor —NO interactions depends on the NO source, the type of exposed cell, the localization of NO within the cell, the duration of NO exposure, and the presence of other free radical species with which NO may interact (Tarr 2006). In general, NO produced by host macrophages and NK cells mediates the anti-tumor response (Roshni 2003). In contrast, the pro-tumorigenic role of NO is ascribed to the intrinsic potential of tumor cells to generate this molecule and accordingly auto-regulate their own growth (Lechner 2005). NO directly influences the growth of tumor cells through electron donation and reaction with transition metals such as iron, zinc and copper and therefore modifies the enzymatic and transcriptional factor activity. Through generation of new radicals, NO indirectly mediates further destruction of cellular components (Li 2005, Tarr 2006, Lechner 2005).
Several active antitumour agents are nowadays available; however, cancer drug design is still a great challenge for numerous scientists. The search is aimed at finding substances with improved efficacy, reduced side-effects and suitable administration routes. A novel therapeutic approach of particular interest in the prevention and/or treatment of cancer is represented by NO-donating nonsteroidal antiinflammatory drugs (NO-NSAIDs).
NO-NSAIDs consist of NSAIDs to which a NO-donating group is covalently attached via an aromatic or aliphatic spacer (see Rigas and Kashfi 2004). Although these drugs share some pharmacological properties with their parent compounds, current data suggest that their structural modification is responsible for enhanced potency and diminished toxicity (Keeble 2002).
NO-NSAIDs are effective in the Alzheimer's disease and in cardiovascular, rheumatological, and lung diseases (Del Soldato et al 1999). The combination of cyclooxygenase-inhibition property of NSAIDs with tumoricidal potential of NO makes these drugs a perfect candidate for the treatment of malignant diseases (see Rigas and Kashfi 2004).
It has been demonstrated that different NO-NSAIDs affect cancer cell growth both in vitro and in vivo. These drugs possess strong anti-proliferative and pro-apoptotic potential against human bladder, colon, prostate, lung, pancreatic, and tongue cancer cells and leukemia cell lines (Kashfi et al 2003, Yeh 2004, Huguenin 2005, Huguenin 2004a, Huguenin 2004b, Gao 2005, Nath 2004, Spiegel 2005). Moreover, NO-aspirin and NO-indomethacin are effective against gastrointestinal cancerogenesis in rats and mice (Bak 1998, Williams 2004, Rao). NO-donating aspirin prevented pancreatic cancer in a hamster tumor model (Ouyang 2006). The exact mechanisms responsible for the action of these drugs are not yet completely understood, but it is believed that the potential targets are NF-κB, inducible NO-synthase and cyclooxygenase (Rigas rew 2004).
It has recently been shown that an isoxazoline compound, (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) possesses strong immunomodulatory properties. VGX-1027 protects mice against the lethal effects of LPS through inhibition of TNF-α synthesis from macrophages and/or T-cells (Stojanovic et at in press). Moreover, administration of VGX-1027 to NOD mice with spontaneous or accelerated forms of diabetes or with immunoinflammatory diabetes induced with multiple low doses of streptozotocin, significantly reduces diabetes progress (Stosic-Grujicic et al 2006).